Dengue is considered a high priority emerging viral disease by the WHO, as over 1 billion people in the world are at risk for dengue hemorrhagic fever (DHF). In dengue endemic countries such as the Philippines, there is an urgent need for a dengue vaccine;however, there is also major concern that widespread use of a vaccine may increase the risk for DHF. Thus, it is critical that reproducible correlates of protective immunity be identified. The goal of this proposal is to identify correlates of protective immunity against dengue in a prospective study of dengue virus infections during infancy. Unlike older children, infants manifest symptomatic dengue (including DHF) following primary DV infections that are modified by pre-existing, maternally-acquired, humoral immunity. The unique immunological conditions of infancy provide the most unadulterated setting to define protective immune correlates. The first aim of this project will be to define levels of serotype-specific neutralizing antibodies (Abs) associated with protective immunity against symptomatic dengue. Neutralizing Ab titers in blood samples collected from Filipino infants before DV infection, and predicted neutralizing Ab titers at the time of illness, will be correlated with disease severity rankings and peak viremia levels. Neutralizing Ab titers at which infants developed symptomatic dengue will be determined. The second aim will be to delineate risk factors contributing to the pathogenesis of DHF in infants. From pre-illness blood samples, the association of Ab neutralizing capacity or enhancement of infection with DHF will be measured while controlling for other potential covariates. The covariates will include measures representing viral load and infant host immune responses. Finally, the third aim will be to strengthen the capacity for diagnosis and research on dengue in the Philippines. A collaborative and international consortium has been formed to advance dengue research in the Philippines. The research will generate vital data for the effective testing of dengue vaccines and future public health vaccination campaigns throughout the region.